The macrophage cell functions as the primary phagocytic mediator of the immune system, and has important roles in regulating inflammation and clearance of cellular debris. Macrophages are thus intimately involved in many diseases. Such involvement can be beneficial, as occurs with phagocytosis of micro-organisms, or deleterious, as with inappropriate macrophage activation leading to overwhelming inflammation as in sepsis, or chronic inflammation in obesity, diabetes, atherosclerosis, and the metabolic syndrome. Abnormal accumulation of cellular components as occurs in Gaucher's disease (genetic deficiency of beta-glucosidase), other lysosomal storage diseases, and possibly in Alzheimer's disease and atherosclerosis can also be seen with macrophage dysfunction. Macrophages cycle through immune tissue in the gut, where, through the action of specific cellular receptors, they phagocytose micro-organisms present in the diet. These macrophages then disperse throughout the body, as they differentiate in specific tissues. I propose to use a novel yeast-based therapeutic strategy to specifically target disease-causing biochemical pathways in the macrophage. In the gut, macrophages readily engulf yeast particles present in the intestinal lumen, providing a novel therapeutic strategy to target this cell line. I will test this novel strategy in in vitro assays using the phagocytic mouse macrophage cell line RAW264. To demonstrate the in vivo utility of this approach, I will use available mouse models of diet-induced obesity and diabetes, Gaucher's disease, and a model of sepsis with LPS-induced systemic inflammation. I will use this approach to develop broadly-applicable, yeast-based therapeutics to target macrophage pathways, and to ultimately safely and efficiently treat a wide range of rare and common diseases.